Hypertension has assumed the form of a grave problem all over the world. In US 23% people are suffering from hypertension. Over three-quarters of women aged 75 or over and 64% of men aged 75 or over have hypertension. (Health, United States, 2002, Table 68). Annually, hypertension cause 23,761 deaths and there are 8.6 deaths per 100,000 population in 2000 (National Vital Statistics Report, Vol. 50, No. 15).
In India, it has been estimated that 10-20% people suffer from hypertension and with increasing urbanization, problem is compounding. Even in India, According to analysis, the prevalence of Hypertension among adults in India is 11%. There is increasing trend in the prevalence of hypertension especially of systolic level. The incidence is more in urban than in rural population. Prevalence is slightly more in women (Gupta, 1997). Cardiovascular deaths in India are estimated to be 2.5 million per year and by 2020 it will be the leading cause of death (Enas et al 1996). This provides window to our future as we urbanize and adopt unhealthy life styles.
Angiotensin Converting Enzyme: Its Physiology
In the development of blood pressure Renin Angiotensin Aldosteron System (RAAS) plays a major role (Petrillo et al, 1982). It interacts with Kallikrein-Kinin-Prostaglandin System (KKP) to regulate blood pressure. ACE, as it is well known, plays a pivotal role in both the system and helps in keeping homeostasis in blood pressure. The key components of RAAS include Renin, Angiotensinogen, Angiotensin Converting Enzyme, Angiotensin-I, Angiotensin-II & Aldosterone.
Increased ACE activity has also been linked to the hypertrophy of endothelial cells in vasculature by decreasing apoptosis. It causes the narrowing of lumen of vessels, which results in increased blood pressure. High ACE activity also contributes to oxidative stress.
Kallikrein-Kinin-Prostaglandin is an alternative blood controlling system (FIG. 1) which is influenced by ACE. Kallikrein is a serine protease glycoprotein synsthesised in liver. It acts upon kininogens producing Bradykinin. Bradykinin synthesizes prostaglandins and nitric oxide (NO) that cause the relaxation of smooth muscles leading to a decrease in blood pressure. Angiotensin converting enzyme degrades Bradykinin thus augmenting the blood pressure (Bhoola et al, 1999).
Interaction of Substrate of Angiotensin Converting Enzyme with Its Active Site
Angiotensin converting enzyme (ACE) plays an important role in both above-mentioned systems.
Angiotensin converting enzyme (MW 150-180 KD) is a membrane bound glycoprotein (Ehlers et al, 1989). It has two homologous domains: N-domain and C-domain. It is a Zn metalloprotease (Ehlers et al, 1989) and removes a dipeptide (His-Leu) from C-terminal of Ang-I (FIG. 2) and converting it to Ang-II, which is a potent vaso-constrictor. The active site of ACE has subsites S1, S1′ and S2′. The substrate of ACE, Angiotensin-I, makes hydrophobic interaction with subsites S1, S1′, S2′. While Zn2+ & its coordinated-water molecule are present in a fourth subsite. The substrate gets oriented in such a way that it interacts with zinc-coordinated water molecule as shown in the FIG. 2. The glutamate polarizes and activates water molecule to hydrolyze Angiotensin-I into Angiotensin-II and a dipeptide. Increased ACE activity leads to enhanced production of Ang-II and degradation of bradykinin leading to increased BP.
Inhibition of ACE
From above, it can be concluded that ACE by regulating blood pressure is the hub of RAAS and KKP. So it may be deduced that molecules that can reduce ACE activity can be used to counter hypertension because inhibition of ACE leads to two major effects:    (1) Decrease in the conversion of angiotensin I to angiotensin II diminishes the effect of RAAS and thus relaxing the smooth muscles and reduce the production of aldosterone resulting in decrease of blood volume and blood pressure (Giudicelli et al, 1995).    (2) Decrease in bradykinin degradation in KKP system. Bradykinin, when interacts with B2 receptors at endothelial cells, causes the release of endothelium-derived relaxing factors like nitric oxide (NO) and prostaglandin-prostacyclin which cause relaxation of smooth muscles leading to a decrease in BP (Giudicelli et al, 1995).New Aspects of Inhibition of ACE
Recent reports suggest that advantages of ACE inhibition go beyond its conventional roles because ACEIs    (1) Decrease in hypertrophy that may decline the chances of atherosclerosis (Chobanian et al, 1990).    (2) Decrease in oxidative stress by reducing the formation of superoxide anions(Munzel and Keaney, 2001)    (3) Decrease in tissue factor activity that can prevent the development of atherosclerosis (Napoleone et al, 2000).    (4) Decrease in ACE activity can increase the level of Ac-SDKP and it can be used as anti cancer therapy (Azizi et al, 1996).
In view of the above-mentioned roles of ACE inhibitors in various disorders, several groups of researchers are engaged in developing drug targets as angiotensin converting enzyme inhibitors.
Current Status of Hypertension Therapies:
Angiotensin Converting Enzyme Inhibitors (ACEIs)
Several vasodilating agents have been synthesized in treatment of congestive heart failure and hypertension Nitrates like isosorbide mononitrate and glyceryl trinitrates are used to counter hypertension (Winbury and Gabel, 1967) but they have a short duration of action (Cohn, Johnson and Ziesche et at, 1991). A diuretic like thiazide increases the excretion of water and along with it sodium. A decrease in sodium leads to hypovolumia resulting in decreased BP. One of the main shortcoming of diuretics is hypokalemia (Brater, 1998). Ca+ plays an important role in muscle contraction. Ca+ channel blockers inhibit influx of Ca+ and do not let the blood pressure rise (Weiner, 1994). Side effects of headache, dizziness and flushing along with peripheral edema are most prominent with Ca channel blockers (Psaty et al, 1995). β-blockers are also among the font line therapy for hypertension. They block the sympathic beta-receptors, which prevent sympathic stimulation of heart rate and cardiac metabolism. Side effects of Beta-blockers are light-headedness, postural hypotension, cold extremities, gastric upset with heartburn, diarrhea and impotence (Quyyumi et al, 1984).
Renin-Angiotensin-Aldosteron System plays the pivotal in development of hypertension. The main acting agent of this system is Ang II, which is a potent vasoconstrictor. There are two main strategies that do not let the Ang II elicit its vasoconstrictive effects. First is AT1 receptor antagonist, which do not let Ang II bind to its AT1 receptors (Goodfriend et al, 1996). Second therapy dealing with RAAS is Angiotensin Converting Enzyme Inhibitors. These inhibitors competitively bind to the active site of ACE and do not let natural substrates (Ang I & Bradkinin) bind to the active site. Captoprils, Enalpril are main ACE inhibitor.
ACEIs are the most important among the drugs controlling hypertension. All the drugs currently available in the market have a more or less similar mode of action. These drugs inhibit the activity of ACE as depicted in the FIG. 1 that leads to decreased formation of Ang II reducing BP.
The main drugs currently available in the market are captopril, enalpril, fosinopril, ramipril and lisinopril.
Captopril is a derivative of proline and D-2-Methyle-3-mercaptopropionic acid whose SH group efficiently interacts with Zn in active site and replaces the water molecule. (Cushman and Ondetti, 1991).
Enalpril has proline and alanine derived moiety whose COO− group interacts with Zn in active site. It is a prodrug that is converted by esterase activity in liver to more active enalprilate (Patchett et at, 1980).
Fosinopril is a derivative of proline and acetic acid derivative with phosphate group that interacts with Zn. Its absorption is rapid. By esterase activity it is converted to fosinoprilate (Singhvi et al, 1988).
Ramipril is a carboxylated dipeptide inhibitor prodrug. In body it is converted into diacid ramiprilate (Vasment and Bender, 1989).
Limitations of Current ACE Inhibitors
    (1) Since most of the ACE inhibitors, synthesized so far, are peptide based. Their peptide nature makes them susceptible to proteolytic degradation and the body excretes them. Due to this reason, ACE inhibitors show less bioavailability and therefore repeated and larger doses are needed to have the desired effects (Gavras and Gavras, 1980).    (2) Sometimes ACE inhibitors lead to accumulation of bradykinin in air passages resulting in bronchospasm and dry-cough (Israili and Hall, 1992).    (3) ACE inhibitor therapy is some times associated with angioedema in which watery fluid is collected under skin, mucous membrane or subcutaneous tissue that sometimes erupt to form boils on skin (Israili and Hall, 1992).    (4) The ACE inhibitors, due to presence of different functional groups, cause rashes, ski irritation, neutropenia and taste alteration (DiBianco, 1986).    (5) Most of the ACE inhibitors cause hypotension. The frequency of hypotension is higher in case of diuretic intake (Hodsman et al, 1983).    (6) They also cause a decline in renal function. During ACE inhibition efferent arteriolar resistance decreases and glomerular filtration declines (Hricik et al, 1983).    (7) ACE inhibitors also cause hyperkalemia because aldosterone is inhibited (Warren and O'Connor, 1980).Peptidomimics: A New Approach
The side effects of these inhibitors have resulted in renewed efforts in modifying the available drugs or developing new drugs with minimum side effects and longer bioavailability. Despite the significant efforts to develop ACE inhibitors devoid of the above said side effects, progress has been disappointed. Moreover currently available ACEIs are peptide-based compounds which are proteolysed by various proteases and excreted by body.
However to the best of our knowledge, no attempt has been made to modify the peptidic nature of these inhibitors in order to inhibit the proteolytic cleavage by various proteases to enhance the longevity as well as their better interaction in the active site. A new emerging concept in the form of peptidomimics seems to be the right answer to this problem (Beelay, 1994).
Peptidomimcs are synthesized by combining peptidic moiety to nonpeptidic moiety. The nonpeptide moieties used include unusual amino acids, some non-toxic, pharmacophoric heterocyclics and diphenyls. These peptidomimics cam be used as ACE inhibitor because they can be resistant to proteolysis and have good interaction with active site.